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2.
Clin Infect Dis ; 2020 Nov 09.
Article in English | MEDLINE | ID: covidwho-1205573

ABSTRACT

BACKGROUND: Limited prior data suggest that preexisting liver disease is associated with adverse outcomes among patients with coronavirus disease 2019 (COVID-19). Fibrosis-4 (FIB-4) is a noninvasive index of readily available laboratory measurements that represents hepatic fibrosis. We evaluated the association between FIB-4 at the early stage of infection and COVID-19 outcomes. METHODS: FIB-4 was evaluated at admission in a cohort of 267 patients admitted with early-stage COVID-19 confirmed through reverse-transcription polymerase chain reaction assay. Hazard of ventilator use and of high-flow oxygen was estimated using Cox regression models controlled for covariates. Risks of progression to severe disease and of death/prolonged hospitalization were estimated using multivariable logistic regression models. RESULTS: Forty-one (15%) patients progressed to severe disease, 36 (14%) required high-flow oxygen support, 10 (4%) required mechanical ventilator support, and 1 died. FIB-4 between 1.45 and 3.25 was associated with a greater than 5-fold (95% confidence interval [CI], 1.2-28) increased hazard of high-flow oxygen use, a greater than 4-fold (95% CI, 1.5-14.6) increased odds of progression to severe disease, and an over 3-fold (95% CI, 1.4-7.7) increased odds of death or prolonged hospitalization. FIB-4 >3.25 was associated with a greater than 12-fold (95% CI, 2.3-68. 7) increased hazard of high-flow oxygen use and an over 11-fold (95% CI, 3.1-45) increased risk of progression to severe disease. All associations were independent of sex, number of comorbidities, and inflammatory markers (D-dimer, C-reactive protein). CONCLUSIONS: FIB-4 at the early-stage of COVID-19 had an independent and dose-dependent association with adverse outcomes during hospitalization. FIB-4 provided significant prognostic value for estimating adverse outcomes among COVID-19 patients.

3.
Preprint | bioRxiv | ID: ppbiorxiv-439793

ABSTRACT

SARS-CoV-2 infection in human can cause medical complications across various tissues and organs. Despite of the advances to understanding the pathogenesis of SARS-CoV-2, its tissue tropism and interactions with host cells have not been fully understood. Existing clinical data have suggested possible SARS-CoV-2 infection in human skeleton system. In the present study, we found that authentic SARS-CoV-2 could efficiently infect human and mouse bone marrow-derived macrophages (BMMs) and alter the expression of macrophage chemotaxis and osteoclast-related genes. Importantly, in a mouse SARS-CoV-2 infection model that was enabled by the intranasal adenoviral (AdV) delivery of human angiotensin converting enzyme 2 (hACE2), SARS-CoV-2 was found to be present in femoral BMMs as determined by in situ immunofluorescence analysis. Using single-cell RNA sequencing (scRNA-Seq), we characterized SARS-CoV-2 infection in BMMs. Importantly, SARS-CoV-2 entry on BMMs appeared to be dependent on the expression of neuropilin-1 (NRP1) rather than the widely recognized receptor ACE2. It was also noted that unlike brain macrophages which displayed aging-dependent NRP1 expression, BMMs from neonatal and aged mice had constant NRP1 expression, making BMMs constantly vulnerable target cells for SARS-CoV-2. Furthermore, it was found that the abolished SARS-CoV-2 entry in BMM-derived osteoclasts was associated with the loss of NRP1 expression during BMM-to-osteoclast differentiation. Collectively, our study has suggested that NRP1 can mediate SARS-CoV-2 infection in BMMs, which precautions the potential impact of SARS-CoV-2 infection on human skeleton system.

4.
Acta Pharm Sin B ; 2021 Mar 11.
Article in English | MEDLINE | ID: covidwho-1126685

ABSTRACT

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a CFDA-approved macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

5.
Am J Chin Med ; 49(3): 543-575, 2021.
Article in English | MEDLINE | ID: covidwho-1119998

ABSTRACT

Chinese medicine (CM) was extensively used to treat COVID-19 in China. We aimed to evaluate the real-world effectiveness of add-on semi-individualized CM during the outbreak. A retrospective cohort of 1788 adult confirmed COVID-19 patients were recruited from 2235 consecutive linked records retrieved from five hospitals in Wuhan during 15 January to 13 March 2020. The mortality of add-on semi-individualized CM users and non-users was compared by inverse probability weighted hazard ratio (HR) and by propensity score matching. Change of biomarkers was compared between groups, and the frequency of CMs used was analyzed. Subgroup analysis was performed to stratify disease severity and dose of CM exposure. The crude mortality was 3.8% in the semi-individualized CM user group and 17.0% among the non-users. Add-on CM was associated with a mortality reduction of 58% (HR = 0.42, 95% CI: 0.23 to 0.77, [Formula: see text] = 0.005) among all COVID-19 cases and 66% (HR = 0.34, 95% CI: 0.15 to 0.76, [Formula: see text] = 0.009) among severe/critical COVID-19 cases demonstrating dose-dependent response, after inversely weighted with propensity score. The result was robust in various stratified, weighted, matched, adjusted and sensitivity analyses. Severe/critical patients that received add-on CM had a trend of stabilized D-dimer level after 3-7 days of admission when compared to baseline. Immunomodulating and anti-asthmatic CMs were most used. Add-on semi-individualized CM was associated with significantly reduced mortality, especially among severe/critical cases. Chinese medicine could be considered as an add-on regimen for trial use.


Subject(s)
/prevention & control , Drugs, Chinese Herbal/therapeutic use , Hospitalization/statistics & numerical data , Medicine, Chinese Traditional/methods , Registries/statistics & numerical data , /drug effects , Adult , Aged , Aged, 80 and over , /virology , China/epidemiology , Drugs, Chinese Herbal/classification , Epidemics , Female , Humans , Male , Middle Aged , Retrospective Studies , /physiology
6.
Fundamental Research ; 2021.
Article | WHO COVID | ID: covidwho-1116731

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a major public health threat worldwide Insight into protective and pathogenic aspects of SARS-CoV-2 immune responses is critical to work out effective therapeutics and develop vaccines for controlling the disease Here, we review the present literature describing the innate and adaptive immune responses including innate immune cells, cytokine responses, antibody responses and T cell responses against SARS-CoV-2 in human infection, as well as in AEC2-humanized mouse infection We also summarize the now known and unknown about the role of the SARS-CoV-2 immune responses By better understanding the mechanisms that drive the immune responses, we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat

7.
Antimicrob Resist Infect Control ; 10(1): 42, 2021 02 25.
Article in English | MEDLINE | ID: covidwho-1105743

ABSTRACT

BACKGROUND: Novel coronavirus pneumonia has been the most serious worldwide public health emergency since being identified in December 2019. The rapid spread of the pandemic and the strong human to human infection rate of COVID-19 poses a great prevention challenge. There has been an explosion in the number of confirmed cases in several cities near Wuhan, including the highest in Honghu, Jinzhou. Owing to the limited admission capacity and medical resources, increasing numbers of suspected cases of COVID-19 infection were difficult to confirm or treat. CASE PRESENTATION: Following the arrival of the Guangdong medical aid team on 11 February, 2020, COVID-19 care in Honghu saw changes after a series of solutions were implemented based on the 'Four-Early' and 'Four-centralization' management measures. The 'Four-Early' measures are: early detection, early reporting, early quarantine, and early treatment for meeting an urgent need like the COVID-19 pandemic. 'Four-centralization' refers to the way in which recruited medical teams can make full use of medical resources to give patients the best treatment. These solutions successfully increased the recovery rate and reduced mortality among patients with COVID-19 in Honghu. CONCLUSIONS: This management strategy is called the 'Honghu Model' which can be generalized to enable the prevention and management of COVID-19 worldwide.


Subject(s)
/prevention & control , /epidemiology , China/epidemiology , Cities/epidemiology , Hospitalization , Humans , Pandemics/prevention & control , Patient Care Management , Public Health , Quarantine , /isolation & purification
8.
Social Anthropology ; n/a(n/a), 2021.
Article in English | WHO COVID | ID: covidwho-1087893
9.
J Biol Chem ; : 100435, 2021 Feb 18.
Article in English | MEDLINE | ID: covidwho-1087033

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic represents a global threat, and the interaction between the virus and Angiotensin-converting enzyme 2 (ACE2), the primary entry receptor for SARS-CoV-2, is a key determinant of the range of hosts that can be infected by the virus. However, the mechanisms underpinning ACE2-mediated viral entry across species remains unclear. Using infection assay, we evaluated SARS-CoV-2 entry mediated by ACE2 of 11 different animal species. We discovered that ACE2 of Rhinolophus sinicus (Chinese rufous horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (wild pig), Capra hircus (goat) and Manis javanica (Malayan pangolin) facilitated SARS-CoV-2 entry into nonsusceptible cells. Moreover, ACE2 of the pangolin also mediated SARS-CoV-2 entry, adding credence to the hypothesis that SARS-CoV-2 may have originated from pangolins. However, the ACE2 proteins of Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (red junglefowl), Notechis scutatus (mainland tiger snake), or Mus musculus (house mouse) did not facilitate SARS-CoV-2 entry. In addition, a natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys. We further demonstrated that the Y217 residue of ACE2 is a critical determinant for the ability of ACE2 to mediate SARS-CoV-2 entry. Overall, these results clarify that SARS-CoV-2 can use the ACE2 receptors of multiple animal species and show that tracking the natural reservoirs and intermediate hosts of SARS-CoV-2 is complex.

10.
Clin Psychol Psychother ; 2021 Feb 16.
Article in English | MEDLINE | ID: covidwho-1085672

ABSTRACT

The aim of current study was to investigate risk perception of COVID-19 pandemic, sleep quality and time change of leisure activity and their correlations with posttraumatic stress disorder (PTSD) in healthcare workers (HCWs) from four designated hospitals in China. Medical staffs (n = 317) from three designated hospitals in Guangdong Province and one designated hospital in Guangxi Province were surveyed on their demographic information, sleep quality and time change of leisure activity, risk perception of pandemic and PTSD symptoms (by using PTSD checklist for DSM-5 (PCL-5)). Hierarchical regression and structural equation model (SEM) were used to examine the correlated factors of PTSD. The prevalence of high level of PTSD symptoms (PCL-5 > =33, a probable diagnosis of PTSD) was 10.7%. Regression analysis found that risk perception (dread: ß = 0.142, p < 0.01; familiarity: ß = 0.203, p < 0.01), sleep quality (ß = 0.250, p < 0.001), time change of leisure activity (ß = -0.179, p < 0.01), were independently correlated with PTSD severity, which was further confirmed by SEM. Locations of COVID-19-related hazards were significant different in cognitive map of risk perception between groups with high and low levels of PTSD symptoms. Risk perception of COVID-19 pandemic influenced PTSD symptoms in HCWs. Adequate time for leisure activity and good sleep quality protected some HCWs against PTSD symptoms under the influence of pandemic. More researches were warranted to understand the path from pre-factors of risk perception to its psychological consequences among HCWs.

11.
ACS Chem Biol ; 16(3): 491-500, 2021 03 19.
Article in English | MEDLINE | ID: covidwho-1084488

ABSTRACT

The outbreak of novel coronavirus SARS-CoV-2 has caused a worldwide threat to public health. COVID-19 patients with SARS-CoV-2 infection can develop clinical symptoms that are often confused with the infections of other respiratory pathogens. Sensitive and specific detection of SARS-CoV-2 with the ability to discriminate from other viruses is urgently needed for COVID-19 diagnosis. Herein, we streamlined a highly efficient CRISPR-Cas12a-based nucleic acid detection platform, termed Cas12a-linked beam unlocking reaction (CALIBURN). We show that CALIBURN could detect SARS-CoV-2 and other coronaviruses and influenza viruses with little cross-reactivity. Importantly, CALIBURN allowed accurate diagnosis of clinical samples with extremely low viral loads, which is a major obstacle for the clinical applications of existing CRISPR diagnostic platforms. When tested on the specimens from SARS-CoV-2-positive and negative donors, CALIBURN exhibited 73.0% positive and 19.0% presumptive positive rates and 100% specificity. Moreover, unlike existing CRISPR detection methods that were mainly restricted to respiratory specimens, CALIBURN displayed consistent performance across both respiratory and nonrespiratory specimens, suggesting its broad specimen compatibility. Finally, using a mouse model of SARS-CoV-2 infection, we demonstrated that CALIBURN allowed detection of coexisting pathogens without cross-reactivity from a single tissue specimen. Our results suggest that CALIBURN can serve as a versatile platform for the diagnosis of COVID-19 and other respiratory infectious diseases.


Subject(s)
Bacterial Proteins/genetics , /diagnosis , CRISPR-Associated Proteins/genetics , CRISPR-Cas Systems , Endodeoxyribonucleases/genetics , RNA, Viral/analysis , /chemistry , Adenoviridae/chemistry , Animals , Fluorescent Dyes/chemistry , Humans , Limit of Detection , Mice, Inbred BALB C , Nucleic Acid Amplification Techniques , RNA Probes/genetics , RNA, Viral/genetics , Specimen Handling , Spectrometry, Fluorescence
12.
Chem Eng J ; : 128788, 2021 Feb 03.
Article in English | MEDLINE | ID: covidwho-1062271

ABSTRACT

Previous observations have been reported that viruses were inactivated using strong irradiation. Here, some new evidence was disclosed by studying the effects of nanosized TiO2 on viral pathogens under a low irradiation condition (0.4 mW/cm2 at UVA band) that mimics the field setting. We showed that photo-activated TiO2 efficiently inhibits hepatitis C virus infection, and week indoor light with intensity of 0.6 mW/cm2 at broad-spectrum wavelength and around 0.15 mW/cm2 of UVA band also lead to partial inhibition. Mechanistic studies demonstrated that hydroxyl radicals produced by photo-activated TiO2 do not destroy virion structure and contents, but attack viral RNA genome, thus inactivating the virus. Furthermore, we showed that photo-activated TiO2 inactivates a broad range of human viral pathogens, including SARS-CoV-2, a novel coronavirus responsible for the ongoing COVID-19 pandemic. In conclusion, we showed that photo-catalyzed nanosized TiO2 inactivates pathogenic viruses, paving a way to its field application in control of viral infectious diseases.

13.
J Travel Med ; 2020 Apr 24.
Article in English | MEDLINE | ID: covidwho-1059297

ABSTRACT

Stringent non-pharmaceutical measures to contain the COVID-19 outbreak in China also significantly reduced the spread of influenza in the winter season 2020.

14.
J Med Chem ; 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-1057678

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript's publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.

15.
J Exp Med ; 218(4)2021 04 05.
Article in English | MEDLINE | ID: covidwho-1035695

ABSTRACT

Virus-specific T cells play essential roles in protection against multiple virus infections, including SARS-CoV and MERS-CoV. While SARS-CoV-2-specific T cells have been identified in COVID-19 patients, their role in the protection of SARS-CoV-2-infected mice is not established. Here, using mice sensitized for infection with SARS-CoV-2 by transduction with an adenovirus expressing the human receptor (Ad5-hACE2), we identified SARS-CoV-2-specific T cell epitopes recognized by CD4+ and CD8+ T cells in BALB/c and C57BL/6 mice. Virus-specific T cells were polyfunctional and were able to lyse target cells in vivo. Further, type I interferon pathway was proved to be critical for generating optimal antiviral T cell responses after SARS-CoV-2 infection. T cell vaccination alone partially protected SARS-CoV-2-infected mice from severe disease. In addition, the results demonstrated cross-reactive T cell responses between SARS-CoV and SARS-CoV-2, but not MERS-CoV, in mice. Understanding the role of the T cell response will guide immunopathogenesis studies of COVID-19 and vaccine design and validation.


Subject(s)
/immunology , Epitopes, T-Lymphocyte/immunology , Host-Pathogen Interactions/physiology , T-Lymphocytes/immunology , T-Lymphocytes/virology , /genetics , Animals , Antibodies, Neutralizing/blood , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/virology , Chlorocebus aethiops , Cross Reactions , Epitope Mapping , Interferon Type I/immunology , Interferon Type I/metabolism , Mice, Inbred BALB C , Mice, Inbred C57BL , Middle East Respiratory Syndrome Coronavirus/immunology , SARS Virus/immunology , /pathogenicity , Vero Cells
16.
Nat Commun ; 12(1): 250, 2021 01 11.
Article in English | MEDLINE | ID: covidwho-1019817

ABSTRACT

Understanding the mechanism for antibody neutralization of SARS-CoV-2 is critical for the development of effective therapeutics and vaccines. We recently isolated a large number of monoclonal antibodies from SARS-CoV-2 infected individuals. Here we select the top three most potent yet variable neutralizing antibodies for in-depth structural and functional analyses. Crystal structural comparisons reveal differences in the angles of approach to the receptor binding domain (RBD), the size of the buried surface areas, and the key binding residues on the RBD of the viral spike glycoprotein. One antibody, P2C-1F11, most closely mimics binding of receptor ACE2, displays the most potent neutralizing activity in vitro and conferred strong protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice. It also occupies the largest binding surface and demonstrates the highest binding affinity to RBD. More interestingly, P2C-1F11 triggers rapid and extensive shedding of S1 from the cell-surface expressed spike glycoprotein, with only minimal such effect by the remaining two antibodies. These results offer a structural and functional basis for potent neutralization via disruption of the very first and critical steps for SARS-CoV-2 cell entry.


Subject(s)
/chemistry , Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/immunology , /immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Binding Sites , /virology , Disease Models, Animal , Epitopes , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Protein Binding , Protein Conformation , Receptors, Virus/immunology , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
17.
Preprint | SciFinder | ID: ppcovidwho-4972

ABSTRACT

The clin merit study of combined detection of PCT and IL-6 on the new coronavirus disease COVID-19

19.
Med Sci Monit ; 26: e928835, 2020 Dec 18.
Article in English | MEDLINE | ID: covidwho-994262

ABSTRACT

BACKGROUND This study summarizes the characteristics of children screened for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and reports the case of 1 child who was diagnosed with SARS-CoV-2 infection in Guangzhou Women and Children's Medical Center and the cases of his family members. MATERIAL AND METHODS The medical records of 159 children who were admitted to our hospital from January 23 to March 20, 2020, were retrospectively analyzed. Samples from pharyngeal or/and anal swabs were subjected to reverse-transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 within 12 h of patient admission; a second RT-PCR test was done 24 h after the first test. RESULTS Of the 159 patients, 151 patients had epidemiological histories, 14 patients had cluster onset, and 8 patients had no epidemiological history but had symptoms similar to coronavirus disease 2019 (COVID-19). The most common symptom was fever (n=125), followed by respiratory and gastrointestinal symptoms. A 7-year-old boy in a cluster family from Wuhan was confirmed with asymptomatic SARS-CoV-2 infection with ground-glass opacity shadows on his lung computed tomography scan, and his swab RT-PCR test had not turned negative until day 19 of his hospitalization. In patients who did not test positive for SARS-CoV-2, influenza, respiratory syncytial virus, and adenovirus were observed. A total of 158 patients recovered, were discharged, and experienced no abnormalities during follow-up. CONCLUSIONS For SARS-CoV-2 nosocomial infections, taking a "standard prevention & contact isolation & droplet isolation & air isolation" strategy can prevent infection effectively. Children with clustered disease need close monitoring.


Subject(s)
/diagnosis , /epidemiology , /methods , Child , Child, Preschool , China/epidemiology , Coronavirus/metabolism , Coronavirus/pathogenicity , Cross Infection/epidemiology , Female , Fever , Hospitalization , Hospitals , Humans , Male , Medical Records , Patient Discharge , Retrospective Studies , /pathogenicity
20.
J Clin Invest ; 130(10): 5235-5244, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-969923

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR-confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20-40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti-SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients' plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/metabolism , Coronavirus Infections/blood , Pneumonia, Viral/blood , Viral Load , Virus Shedding , Adult , Aged , Antibody Specificity , Cross Reactions , Female , Humans , Kinetics , Male , Middle Aged , Pandemics , Severity of Illness Index
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